During the clinically latent phase of HIV-1 infection, it has become clear that lymphoid tissues serve as a major reservoir of virus. However, it is unclear how the initial virus inoculum which establishes the primary infection is transmitted to secondary lymphoid organs. World-wide to date, more than 80% of HIV-1 spread occurs via heterosexual transmission. There is in vivo and in vitro evidence that cells of the Langerhans cell lineage in mucosa and skin be infected with HIV-1, and it has been hypothesized that these cells are involved in the transmission of virus to CD4+ T cells in secondary lymphoid tissues. Using highly purified preparations of blood dendritic cells (thought to be related to Langerhans cells), our preliminary studies in vitro suggest that such cells are highly efficient in uptake and delivery of virus to uninfected CD4+ target T cells. The overall aim of this proposal is to better understand the interaction of HIV-1 with Langerhans cells, and to determine whether such cells, when infected, can in turn productively infect target T cells. This will be accomplished both in controlled in vitro conditions, as well as in vivo. The in vivo studies will utilize a novel chimeric model involving human skin grafted onto RAG-2 gene knockout mice. These mice, which are theoretically superior to SCID mice as immunosuppressed graft recipients, will be used to determine whether Langerhans cell transmission of HIV-1 to T cells can occur within anatomical constraints that are relevant to human disease. Lessons from these studies can be extrapolated to a better understanding of the mechanisms for mucosal infection, systemic spread of HIV-1 to the secondary lymphoid organs, and the potential use of mucosal dendritic cells in vaccine development.